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Utilizing Murine Inducible Telomerase Alleles in the Studies of Tissue Degeneration/Regeneration and Cancer
Published on: April 13, 2015
Inhibitory effect of telomere-mimic phosphorothioate oligodeoxy nucleotides (S-ODNS) on human tumor cell lines
T Saeki1, S Takashima, M Tachibana
1National Shikoku Cancer Center, Ehime University, Matsuyama, Japan. tsaeki@shikoku-cc.go.jp
Abstract:
To clarify the inhibitory effect of telomere-mimic oligonucleotides on human cancer cell lines, we synthesized 18-mers (18T; n = 3), 24-mers (24T; n = 4) and 30-mers (30T; n = 5) of telomere-mimic phosphorothioate oligodeoxy nucleotides [5'-d(TTA GGG)n-3'] and examined their effects on the proliferation of human tumor cells by XTT assay. After 7 days of continuous exposure to 24T and 30T at concentrations ranging from 0.1 to 10 microM, concentration-dependent cell growth inhibition was observed in MCF-7 clone E3, ZR-75-1, MDA-MB 231, Colo 201 and WiDr. All of these cell lines highly expressed telomerase using the telomeric repeat amplification protocol. None of these tumor cell lines were affected by 18T. In MCF-7, ZR-75-1 and Colo 201 cell lines, a more than 50% growth inhibition was obtained by 3 microM of 24T and 30T whereas, in MDA-MB 231 and WiDr cell lines, cell growth inhibition was less than 50%. 30T was more effective than 24T. Estrogen-dependent growth of both MCF-7 and ZR-75-1 was inhibited by 3 microM of 24T and 30T, however, in the absence of estrogen, no growth inhibition was seen. The MCF-10A cell line, which was developed from normal human breast tissue and expressed telomerase only weakly, was inhibited by 10 microM of 18T. In conclusion, these observations indicate that S-ODNs inhibit tumor growth in cell lines expressing telomerase in a concentration-dependent manner and that cell growth inhibition is dependent on the length of S-ODNs. In addition, the short-length S-ODNs may inhibit growth of cells weakly expressing telomerase, but not of cells with high telomerase expression.
Insights
Telomere-mimic oligonucleotides (S-ODNs) show concentration-dependent inhibition of human cancer cell growth, with longer S-ODNs being more effective. Shorter S-ODNs may inhibit cells with weak telomerase activity.
Area of Science:
- Molecular Biology
- Cancer Research
- Oligonucleotide Therapeutics
Background:
- Telomerase is a key enzyme in cancer cell immortalization and proliferation.
- Telomere-mimic oligonucleotides (S-ODNs) are investigated for their potential anti-cancer effects.
- Understanding the structure-activity relationship of S-ODNs is crucial for therapeutic development.
Purpose of the Study:
- To evaluate the inhibitory effect of different lengths of telomere-mimic phosphorothioate oligodeoxy nucleotides (S-ODNs) on human cancer cell lines.
- To determine the relationship between S-ODN length, concentration, and telomerase expression in cancer cell growth inhibition.
- To assess the impact of estrogen on the efficacy of S-ODNs in estrogen-dependent cancer cells.
Main Methods:
- Synthesis of 18-mer, 24-mer, and 30-mer S-ODNs.
- Treatment of human cancer cell lines (MCF-7, ZR-75-1, MDA-MB 231, Colo 201, WiDr) and a normal cell line (MCF-10A) with S-ODNs.
- Quantification of cell proliferation using XTT assay and assessment of telomerase activity using the telomeric repeat amplification protocol.
Main Results:
- 24-mer and 30-mer S-ODNs demonstrated concentration-dependent inhibition of cell growth in highly telomerase-expressing cancer cell lines.
- 30-mer S-ODNs were more effective than 24-mer S-ODNs; 18-mer S-ODNs showed no significant effect on these cell lines.
- Estrogen-dependent growth of MCF-7 and ZR-75-1 cells was inhibited by 24-mer and 30-mer S-ODNs, but not in the absence of estrogen. Weakly telomerase-expressing MCF-10A cells were inhibited by 18-mer S-ODNs at a high concentration.
Conclusions:
- S-ODNs inhibit tumor cell growth in a concentration- and length-dependent manner, correlated with telomerase expression levels.
- The efficacy of S-ODNs is influenced by the length of the oligonucleotide and the telomerase activity of the target cells.
- S-ODNs hold promise as anti-cancer agents, with potential for differential effects based on telomerase expression and hormonal dependence.
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